Although women represent close to half of the smokers in the U.S., how sex and phase of the menstrual cycle affect nicotine dependence is not well understood. Studies suggest that women, compared to men, may be less sensitive to the subjective and reinforcing effects of nicotine. The menstrual cycle phase may affect smoking behavior and the severity of tobacco withdrawal symptoms in female smokers. These sex and menstrual cycle effects could be due to fluctuations of female sex steroid-hormones, estradiol and progesterone, within the menstrual cycle. In a pilot study with overnight abstinent female smokers, we have observed that progesterone treatment attenuates the subjective effects of the first cigarette and craving for cigarettes. We conjecture that the attenuation of nicotine's reinforcing effects by progesterone may contribute to the observed sex and menstrual phase effects on nicotine dependence in humans. The goal of this proposal is to extend our preliminary findings by systematically examining the effects of progesterone on smoking behavior, tobacco withdrawal symptoms and subjective rewarding effects of smoking. This will be a double-blind, placebo-controlled study in which male and female smokers will be randomly assigned to one of the 3 treatment conditions: placebo, low (200 mg/day) or high dose (400 mg/day) of progesterone for four days. Subjects will abstain from smoking for the first 3 days of the treatment period, followed by an ad lib smoking session on day 4. We hypothesize that progesterone treatment, dose-dependently, will reduce smoking behavior, attenuate tobacco withdrawal symptoms, and subjective rewarding effects of smoking in both male and female smokers. By characterizing the progesterone effects on nicotine dependence, this study may provide a better understanding of the mechanisms which mediate the sex and menstrual cycle phase effects on nicotine dependence.